Flies lies in motion: What drosophila can tell us about amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with a prevalence of 1 in 30,000 individuals. Generally diagnosed between 40 and 70 years of age, ALS is accompanied by progressive loss of motor neuron function and a life expectancy of 2-5 years. Although age is considered to be the highest risk factor for ALS, it is clear that the disease has a genetic basis and may also be influenced by environmental factors. Familial ALS (fALS) affects 10% of patients and has been linked to several loci, the most common of which is C9ORF72, a gene of unknown function. The remaining 90% of ALS cases are sporadic (sALS) and remain poorly understood, although some loci have been linked to both fALS and sALS. In recent years a dramatic shift in our thinking about ALS has been catalysed by findings that the RNA binding proteins TAR DNA binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) constitute markers of pathology and when mutated, neural degeneration occurs in human patients. Studies in a wide range of model systems including worms, flies, zebrafish and rodents support the notion that alterations in these RNA binding proteins and RNA metabolism cause motor neuron disease. Together with the recent discovery of GGGGCC repeat expansions in C9ORF72, these studies led to the hypothesis that ALS is a disease of RNA dysregulation. Here we will review the contributions of the fruit fly Drosophila melanogaster to our understanding of ALS with a focus on TDP-43, FUS/TLS and RNA dysregulation as a disease mechanism.